title: BMS-986001, an HIV nucleoside reverse transcriptase inhibitor, does not degrade mitochondrial DNA in long-term primary cultures of cells isolated from human kidney, muscle, and adipose tissue.
abstract: Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) remain the cornerstone of HIV treatment; however, they are associated with toxicities attributed in part to inhibition of mitochondrial DNA (mtDNA) polymerase γ. In this study, we compared the in vitro toxicity profiles of structurally similar NRTIs (BMS-986001 to stavudine and tenofovir to adefovir) that differ by the presence of an acetylene or methyl group, respectively. Primary cultures of human renal proximal tubule epithelium, skeletal muscle myotubes, and differentiated adipocytes were exposed to the NRTIs at the maximum concentration (Cmax) reported for the clinically approved dose (investigational dose for BMS-986001, 600 mg) and a high equimolar concentration (200 μM) for 19 days. After 19 days, BMS-986001 did not significantly decrease mtDNA or cell protein at either concentration in any cell line. In contrast, stavudine significantly decreased mtDNA in all cultures (1.5- to 2.5-fold) (except at Cmax in renal cells) and cell protein in renal cells (1.4- to 2.4-fold). By day 19, at 200 μM, tenofovir significantly reduced mtDNA in adipocytes (1.9-fold) and adefovir significantly decreased mtDNA in all cultures (3.7- to 10.2-fold); however, no significant reduction in mtDNA was observed at Cmax in any cell line. Adefovir also significantly reduced cell protein at both concentrations in renal cells (2.2- to 2.8-fold) and at 200 μM in muscle cells (2.0-fold). In conclusion, BMS-986001 and tenofovir were considerably less cytotoxic than their respective structural analogs, demonstrating that small structural differences can contribute to significant differences in toxicity.
authors.affiliation: Discovery Toxicology, Bristol-Myers Squibb, Princeton, New Jersey, USA.
authors.forename: Faye
authors.initials: F
authors.lastname: Wang
authors.forename: Oliver P
authors.initials: OP
authors.lastname: Flint
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000187:drug effects* / Q000648:ultrastructure; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects; D063065:Organophosphonates / Q000494:pharmacology* / Q000633:toxicity*; D061251:Primary Cell Culture; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D018119:Stavudine / Q000633:toxicity*; D013329:Structure-Activity Relationship; D000068698:Tenofovir; D013936:Thymidine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C583040:BMS-986001; D004272:DNA, Mitochondrial; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; C053001:adefovir; D000068698:Tenofovir; D018119:Stavudine; D000225:Adenine; D013936:Thymidine